Purpose: The questions that we wish to answer in the current study are whether the long term administration of an angiotensin II converting enzyme inhibitor in patients with sickle cell nephropathy 1) prevents or retards the development of renal insufficiency, and 2) reduces proteinuria on a long term basis. Methods: Patients are treated with either Enalapril or placebo. The primary outcome variable is change in the glomerular filtration rate. Results: We now have 5 patients at Duke who remain on the protocol. Fifteen patients initially enrolled in the study, with one withdrawn by physicians owing to an presumed idiosyncratic reaction to the drug (back pain), and one patient who withdrew from the study. Over twenty-four months, eight more patients have been lost to noncompliance/attrition ( 4 males and 4 females). As anticipated, the entire patient population is African-American. Enrollment for the study has ceased at DUMC. A total of 95 patients have been enrolled at the University of North Carolina, Duke University, East Carolina University, and the University of Alabama at Birmingham. An interim analysis was performed for safety and efficacy reasons. Initial review shows that the renal function in both treated and untreated patients is stable at two years demonstrating safety of this therapy. Additionally, there is a suggestion that the treated patients enjoy an incremental improvement in renal function, though the number of observations are small. Importantly, a decrement in the amount of proteinuria was observed in each patient treated with ACE inhibitor whereas no changes in proteinuria are observed in placebo-treated patients at 1 month and over time. There were no difference between males and females in this regard. Thus our interim analysis suggests that the long term by ACE inhibition is effective in ameliorating proteinuria in adults. Future plans: We are currently extending the trial down to age 5 years with continuation of the current and new protocols through the Duke-UNC Sickle Cell Center. We have been given approval by the Institutional Review Board to enroll children, and have three children with biopsy proven sickle nephropathy on ACE-inhibitor therapy. To date, these patients have evidenced a significant reduction in proteinuria from pre-treatment levels. Significance: Angiotensin II converting enzyme inhibitor therapy has been shown to reduce protein excretion in several forms of glomerular disease. This diminution of protein excretion occurs in the presence and absence of systemic hypertension. In human studies, it is reasonably certain that glomerular hypertension plays a role in the pathogenesis of experimental diabetic nephropathy, and angiotensin II converting enzyme inhibitor therapy has a salutary effect. From a previous short term prospective trial, we know that an angiotensin II converting enzyme inhibitor is capable of reducing proteinuria in patients with sickle cell nephropathy for a short interval. Important questions which are being evaluated are whether or not angiotensin II converting enzyme inhibitor therapy, by reducing glomerular capillary hypertension, can ameliorate proteinuria for an extended time and whether or not angiotensin II converting enzyme inhibitor therapy can retard the progressive decline in renal function in sickle cell disease patients with renal insufficiency.